GB2179944A - Mixtures of mono- and disodium salts of fosfomycin - Google Patents

Mixtures of mono- and disodium salts of fosfomycin Download PDF

Info

Publication number
GB2179944A
GB2179944A GB08521832A GB8521832A GB2179944A GB 2179944 A GB2179944 A GB 2179944A GB 08521832 A GB08521832 A GB 08521832A GB 8521832 A GB8521832 A GB 8521832A GB 2179944 A GB2179944 A GB 2179944A
Authority
GB
United Kingdom
Prior art keywords
fosfomycin
mixtures
salts
mono
disodium salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB08521832A
Other versions
GB8521832D0 (en
Inventor
Higom Arturo Torregrosa
Ibanez Matilde Fernandez
Sanchez Millan Garcia
Prieto Agustino Prieto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia Antibioticos Farma SA
Original Assignee
Pharmacia Antibioticos Farma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Antibioticos Farma SA filed Critical Pharmacia Antibioticos Farma SA
Priority to GB08521832A priority Critical patent/GB2179944A/en
Publication of GB8521832D0 publication Critical patent/GB8521832D0/en
Priority to ES555091A priority patent/ES8707248A1/en
Priority to EP86305378A priority patent/EP0213704A3/en
Priority to PT83021A priority patent/PT83021B/en
Priority to AU60756/86A priority patent/AU6075686A/en
Priority to JP61182063A priority patent/JPS6256498A/en
Publication of GB2179944A publication Critical patent/GB2179944A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65502—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a three-membered ring
    • C07F9/65505—Phosphonic acids containing oxirane groups; esters thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Mixtures of fosfomycin monosodium and disodium salts for use by parenteral or oral administration are described, for example containing 60-65 % of the monosodium salt and 40-35 % of the disodium salt.

Description

1
GB2179944A 1
SPECIFICATION
Mixtures of mono- and disodium salts of fosfomycin
5 This invention relates the parenteral and oral use of mixtures of monosodium and disodium salts of the antibiotic FOSFOMYCIN, chemically designated as (—) (cis-1,2-epoxyproply)phosphonic acid. The mixtures subject of this invention are those containing 60-65% of the monosodium salt, of formula
10
15
H.
.H
/
c
CH.
N0^ \ ,°
P-OH
so-
+
Na and 40-35% of disodium salt, of formula
20
25
30
35
40
45
50
55
60
65
H
C —
Ctif
- c
/ \ *
P-0
N0~
0
(Na)
Fosfomycin is an antibiotic discovered in Spain in 1966 which is described in the Merck Index, 10th edition. No. 4137, isolated originally from fermentation broths of a strain of Streptomyces fradiae obtained from a soil sample collected in Javea, Alicante, Spain.
The mono-salts or di-salts of fosfomycin are active against gram-positive and gram-negative bacteria, and therapeutically useful in the treatment of infections caused thereby. Its antibiotic spectrum comprises the following species:
Aerobes
Staphylococcus aureus Streptococcus pyogenes Streptococcus pneumoniae Streptococcus faecalis Neisseria meningitidis Neisseria gonorrhoea Haemophilus influenzae Legionella pneumophila Escherichia coli Indole (—) Proteus spp. Indole (+) Proteus spp.
Anaerobes Peptococcus spp. Peptostreptococcus spp.
Klebsiella spp.
Enterobacter spp.
Serratia marcescens Pseudomonas aeruginosa Salmonella spp.
Shigella spp.
Campylobacter fetus jejuni Yersinia enterocolitica Acinetobacter calcoaceticus Vibrio cholerae Aeromonas spp.
Fusobacterium spp. Clostridium spp.
The salts of alkaline metals and alkaline-earth metals, such as mono- and di-salts of sodium, potassium, calcium, magnesium, etc., have been known for a long time. Also known are salts formed with amines, such as a-phenethylamine, quinine, lysine, procaine, etc., which can be mono- or di-salts.
The salts of fosfomycin currently used in antibiotherapy are calcium salt for oral administration and disodium salt for parenteral administration (intramuscular and intravenous).
The mixture of mono and disodium salts 60-65/40-35) displays advantages over those used at present. In parenteral administration, disodium fosfomycin gives very alkaline aqueous solutions, thus requiring the use of acids to achieve a physiological pH, and also increases the tonicity of the solution, and because of this results in painful intramuscular administration, with the additional limitation due to the high sodium content.
The mixture of mono- and disodium salts reduces or avoids the side effects of the disodium salt, as the pH of the solution of the mixture is closer to the physiological pH and therefore the use of neutralizing acids is not required. Moreover the mono and disalt mixture reduces the sodium problem.
In oral administration, the plasma concentrations obtained in a crossed test with the calcium
10
15
20
25
30
35
40
45
50
55
60
65
2
GB2179944A 2
salt and the mixture of mono and disodium salts, at a single oral dose of 1 g, show a significantly higher bioavailability than the calcium and disodium salts.
The following example is illustrative of the process subject of the invention and should not be considered to be limitative.
5 Example: Preparation of the mixture of monosodium salt
10
15
Hv xc — c" / \ ,°
CH, P-OH
3 vo-
and disodium salt
20
H.
.H
C'
CH
P-O"
sO~
+ Na
(Na)
10
15
20
of (—) (cis-1,2-epoxyproply)phosphonic acid:
Prepare a solution of 20 g of mono (+)-a-phenethylamine salt of fosfomycin in methanol. Add 25 5.7 g of sodium methoxide and mix for 15 minutes. The mixture of mono- and disodium salts of 25 fosfomycin is precipitated with acetone. About 10 g of the mixture of fosfomycin salts were obtained, being characterized by the parameters detailed below:
N.M.R. (in deuterium oxide)
30 ppm(d) 30
1.48 (d,d; J=5.7 and 0.7 Hz; 3H, CH3)
2.85 (d,d; J=5.4 and 21.3 Hz; 1H, CH)
3.30 (m; J=5.4 1H, CH)
35 I.R. Spectrum (in KBr pressed discs) 35
The IR spectrum displays characteristics bands at 1416, 1380, 1339, 1268, 1200, 1040, 1000, 950, 920, 860, 735 cm \
40
45
pH (5% water solution): 6.50 Sodium content (%): 18.2%
Microbiological assay: Against Proteus mirabilis ATCC 21100; antibiotic activity equivalent to 800 //g/mg of free fosfomycin acid.
PHARMACEUTICALS FORMS Oral administration
CAPSULES (500 mg)
Fosfomycin (mono and disodium salts mixture) 50 Magnesium stearate Lactose c.s.p.
SACHETS (500 mg)
Fosfomycin (mono and disodium salts mixture)
Fruit flavour 55 Sucrose c.s.p.
SACHETS (1 g)
Fosfomycin (mono and disodium salts mixture)
Fruit flavour Sucrose c.s.p.
60
Parenteral administration (intramuscular or intravenous) VIAL 1 g
Fosfomycin (mono and disodium salts mixture)
VIAL 4 g
65 Fosfomycin (mono and disodium salts mixture)
500 mg 4 mg 620 mg
500 mg 150 mg 3,500 mg
1,000 mg 150 mg 4,200 mg
1,000 mg 4,000 mg
40
45
50
55
60
65
3
GB2179944A 3
For intramuscular administration use ampoules containing local anaesthesics, example:
Lidocaine HCI 25 mg
Water for injection c.s.p. 4 ml

Claims (1)

  1. 5 CLAIMS 5
    1. The use of mixtures of fosfomycin monosodium and disodium salts for parenteral and oral administration.
    2. Pharmaceutical compositions for oral and parenteral administration, containing as an active ingredient mixtures of monosodium and disodium salts defined in claim 1, together with excipi-
    10 ents and/or pharmaceutical^ acceptable carriers. 10
    3. A process for preparing the mono- and disodium salts of fosfomycin and mixtures thereof, characterized in that the fosfomycin phenethylamine salt is reacted with sodium methoxide in alcoholic medium, and the salts are precipitated by addition of a solvent.
    4. A process according to claim 3, wherein the alcohol is selected from a straight- or
    15 branched chain-monohydroxyl alcohol with a number of carbon atoms comprised between 1 and 15 5 of said alcohols, preferably methanol.
    5. A process according to claim 3, wherein the precipitating solvent is one of the following:
    ethyl acetate, acetone, isopropanol, ethanol, petroleum ether, ethyl ether, or a mixture of thereof, preferably acetone or isopropanol.
    20 6. A method for treating human or animal infections consisting of administering thereto one 20 of the pharmaceutical compositions defined in claim 2.
    Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8817356, 1987.
    Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.
GB08521832A 1985-09-03 1985-09-03 Mixtures of mono- and disodium salts of fosfomycin Withdrawn GB2179944A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
GB08521832A GB2179944A (en) 1985-09-03 1985-09-03 Mixtures of mono- and disodium salts of fosfomycin
ES555091A ES8707248A1 (en) 1985-09-03 1986-05-19 Mixtures of mono- and disodium salts of fosfomycin.
EP86305378A EP0213704A3 (en) 1985-09-03 1986-07-14 Mixtures of mono- and disodium salts of fosfomycin
PT83021A PT83021B (en) 1985-09-03 1986-07-18 Process for the preparation mono-and disodium salts fosfomycin and mixtures thereof
AU60756/86A AU6075686A (en) 1985-09-03 1986-07-31 Pharmaceutical compositions of mono-and disodium salts of fosfomycin
JP61182063A JPS6256498A (en) 1985-09-03 1986-08-04 Use of mixture of sodium salt and disodium salt of phosphomycin, pharmaceutical composition and production of said salts and mixture

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB08521832A GB2179944A (en) 1985-09-03 1985-09-03 Mixtures of mono- and disodium salts of fosfomycin

Publications (2)

Publication Number Publication Date
GB8521832D0 GB8521832D0 (en) 1985-10-09
GB2179944A true GB2179944A (en) 1987-03-18

Family

ID=10584632

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08521832A Withdrawn GB2179944A (en) 1985-09-03 1985-09-03 Mixtures of mono- and disodium salts of fosfomycin

Country Status (6)

Country Link
EP (1) EP0213704A3 (en)
JP (1) JPS6256498A (en)
AU (1) AU6075686A (en)
ES (1) ES8707248A1 (en)
GB (1) GB2179944A (en)
PT (1) PT83021B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA021876B1 (en) * 2010-09-20 2015-09-30 ЛИМОНОВ, Виктор Львович Pharmaceutical composition having antimicrobial and anti-inflammatory activity for parenteral administration, process for preparing same

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015070131A1 (en) * 2013-11-11 2015-05-14 Forest Laboratories Holdings Limited Compositions and methods of treatment comprising fosfomycin disodium
EP3812007A1 (en) 2019-10-24 2021-04-28 Sandoz Ag New formulations of fosfomycin with reduced sodium content for parenteral use and methods of producing the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1233286A (en) * 1968-05-15 1971-05-26
GB1236957A (en) * 1968-05-15 1971-06-23 Merck & Co Inc Preparation of (cis-1,2-epoxypropyl)phosphonic acid and derivatives
GB1267091A (en) * 1968-05-15 1972-03-15

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3914231A (en) * 1970-09-04 1975-10-21 Merck & Co Inc ({31 )(Cis-1,2-epoxypropyl)-phosphonic acid and salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1233286A (en) * 1968-05-15 1971-05-26
GB1236957A (en) * 1968-05-15 1971-06-23 Merck & Co Inc Preparation of (cis-1,2-epoxypropyl)phosphonic acid and derivatives
GB1267091A (en) * 1968-05-15 1972-03-15

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA021876B1 (en) * 2010-09-20 2015-09-30 ЛИМОНОВ, Виктор Львович Pharmaceutical composition having antimicrobial and anti-inflammatory activity for parenteral administration, process for preparing same

Also Published As

Publication number Publication date
EP0213704A2 (en) 1987-03-11
GB8521832D0 (en) 1985-10-09
PT83021A (en) 1986-08-01
JPS6256498A (en) 1987-03-12
ES555091A0 (en) 1987-07-16
PT83021B (en) 1987-12-04
AU6075686A (en) 1987-03-05
EP0213704A3 (en) 1987-09-16
ES8707248A1 (en) 1987-07-16

Similar Documents

Publication Publication Date Title
KR100574153B1 (en) Crystal forms of azithromycin
US5137919A (en) Effect of N,N,N,-trimethylsphingosine on protein kinase C activity melanoma cell growth in vitro; metastatic potential in vivo and human platelet aggregation
PH26391A (en) Method for treating gastrointestinal disorders
EP0130482B1 (en) Diaminocyclohexane platinum complexes, process for preparing same and pharmaceutical compositions containing same
EP2185143B1 (en) Antimicrobial parenteral formulation
EP0552137B1 (en) Esters of acyl carnitines with long-chain aliphatic alcohols and pharmaceutical compositions containing same having antibacterial activity
FR2487358A1 (en) NEW DERIVATIVES OF LINCOMYCIN
US5248824A (en) Method of preparing N,N,N-trimethylsphingosine
RU2204565C2 (en) Bismuth salts of antibiotics of group moenomycin, method of their preparing, their using and medicinal agents containing such salts
GB2179944A (en) Mixtures of mono- and disodium salts of fosfomycin
Schnitzer et al. Chemotherapeutic studies with 2, 4-dimethoxy-6-sulfanilamido-1, 3-diazine (Madribon)
JPS6084288A (en) Cyanoquinonamine acetate and its production
US4675315A (en) Antimicrobial salt of fosfomycin with imidazole
JPH0631301B2 (en) Antibacterial 9-deoxo-9a-allyl and propargyl-9a-aza-9a-homoerythromycin A derivatives
Butler et al. Indanyl carbenicillin: Chemistry and laboratory studies with a new semisynthetic penicillin
JP2002530326A (en) Use of phosphonoformic acid derivatives for the treatment of infectious diseases
PT88568B (en) PROCESS FOR THE PREPARATION OF SUCROSE DERIVATIVES
US20100152429A1 (en) Sodium salt of disaccharide compound, method for producing the same, and use of the same
US20090054355A1 (en) Proliferation Inhibitor Of Helicobacter Pylori Including Alpha-N-Acetyl-Glucosaminyl Bond-Containing Monosaccharide Derivatives
GB2085882A (en) Aprosamine derivatives
US5091523A (en) Mitomycin derivatives having reduced bone marrow toxicity, processes for their preparation, and the uses thereof
US3013942A (en) Therapeutic erythromycin ester compositions
US3783159A (en) Pharmaceutical compositions containing kanamycin embonate
US3770809A (en) Thiamphenicol derivatives
US4169890A (en) Pharmaceutical composition containing 5"-amino-3',5"-dideoxy-ribostamycin and intermediate compounds

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)